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«DIVISION OF SPECIAL PATHOGEN AND TRANSPLANT PRODUCTS Biomarker Qualification Detection of Galactomannan in Broncho-Alveolar Lavage Fluids by Platelia ...»

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DIVISION OF SPECIAL PATHOGEN AND TRANSPLANT PRODUCTS

Biomarker Qualification

Detection of Galactomannan in Broncho-Alveolar Lavage Fluids

by

Platelia Aspergillus Enzyme Immunoassay

(BioRad Laboratories, USA and Sanofi Diagnostics, France)

Sponsor: On behalf of Mycoses Study Group:

Peter G. Pappas, M.D. Paul E. Verweij, M.D.

Division of Infectious Diseases Department of Medical Microbiology University of Alabama, Birmingham University Hospital Nijmegen Birmingham, AL 35294 The Netherlands

Reviewers:

Microbiology: Simone M. Shurland Ph.D., Medical Officer: Elizabeth O’Shaughnessy, M.D.

Statistics: Cheryl Dixon, Ph.D.

Concurrence:

Microbiology Team Leader: Shukal Bala, Ph.D.

Statistics Team Leader: Karen Higgins, Ph.D.

Division Director: Renata Albrecht, M.D.

Completion Date: January 4, 2011 Biomarker Qualification Page 2 Galactomannan Detection by Platelia Aspergillus EIA in BAL fluids Mycoses Study Group

TABLE OF CONTENTS

1. Executive Summary

2. Introduction and Background

2.1. Invasive Aspergillosis

2.1.1. Disease

2.1.2. Diagnosis

2.1.3. EORTC/MSG Criteria for Invasive Fungal Diseases

2.1.4. Microbiology of Aspergillus species

2.2. Platelia Galactomannan EIA

3. Performance of the Platelia Aspergillus EIA

3.1. In Vitro Studies

3.2. Animal Studies

3.3. Clinical Studies

3.3.1. Sensitivity

3.3.3. Predictive Values

3.3.4. Comparison with other diagnostic methods

3.3.5 Limitations

3.4 General Statistical Implications

4. Conclusions

5. References

APPENDIX I - In vitro Studies

APPENDIX II - Animal Studies

APPENDIX III - Clinical Microbiology Studies

Biomarker Qualification Page 3 Galactomannan Detection by Platelia Aspergillus EIA in BAL fluids Mycoses Study Group

1. Executive Summary

The sponsor is seeking approval to include a positive galactomannan assay in bronchoalveolar lavage (BAL) fluids as the only microbiologic criteria, in conjunction with clinical and radiological findings, for the diagnosis of patients with probable invasive aspergillosis in predisposed neutropenic patients with hematologic cancer or recipients of hematopoietic stem cell transplants (HSCT). This is for the purpose of enrollment in clinical trials for treatment of invasive aspergillosis according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The EORTC/MSG criteria were first published in 2002 and were used to classify patients with proven, probable, or possible invasive fungal infection and were used in a majority of the studies included in this review (Table 1A and 1B). The EORTC criteria were recently updated and published by de Pauw et al. (2008).

In 2003, the US FDA Center for Devices and Radiological Health (CDRH) approved the Platelia Aspergillus enzyme immunoassay (EIA; BioRAD Laboratories) for testing of serum samples. The brochure recommends that results of the Platelia Aspergillus EIA be used in conjunction with other standardized methods such as clinical, radiological, culture and histopathological findings for diagnosis of invasive aspergillosis. A serum sample is considered positive at a cut-off index ≥ 0.5 based on testing of two aliquots of the same sample and another sample collected at a different time. However, the performance of the galactomannan assay in biological samples other than serum for the diagnosis of invasive pulmonary aspergillosis (IPA) has not been evaluated by CDRH.

The sponsor proposes a positive galactomannan test, Platelia Aspergillus EIA (hereforth referred to as galactomannan assay), in BAL as a “stand-alone” microbiological criterion to define “probable” invasive pulmonary aspergillosis (IPA) based on the EORTC/MSG criteria (2008). A positive galactomannan test will be based on testing of a single BAL sample at a cut-off of ≥ 1.0.

In Vitro Studies In vitro studies show that the Platelia Aspergillus EIA in BAL fluids, spiked with known moderate and high concentrations of Aspergillus galactomannan, has good precision for detection of galactomannan (CV% range 2-12%). The galactomannan assay in BAL fluids also demonstrate good reproducibility (96%) between runs at a cut-off of ≥1.0, between days when retested on the same aliquot as well as when retested after freezing.

However, caution may be needed in interpreting a single positive test at indices between

0.5 and 0.9 as the reproducibility was low (75%). It will be appropriate to test two aliquots of the same BAL specimen.

In vitro studies demonstrate that false positives can occur due to cross reactivity with Histoplasma capsulatum and other fungi such as Penicillium sp., Paeliocymyces sp.

Alternaria sp., Geotrichum sp. (for details see Table 7) and with Plasmalyte®, a solution used during bronchoscopy for collection of BAL fluid samples.

Biomarker Qualification Page 4 Galactomannan Detection by Platelia Aspergillus EIA in BAL fluids Mycoses Study Group Animal Studies In experimentally induced neutropenic mice, rats, and rabbits with invasive Aspergillus infection, the galactomannan index in BAL fluids ranged from 0.75 to 4.0. The overall sensitivity of the galactomannan was variable and ranged from 25% to 100%, depending on the day post-infection and the cut-off index. However, the overall specificity (100%) and PPV (100%) remained consistent in all animal studies.





Becker et al. (2000), study in rats showed reduced sensitivity of the galactomannan assay in BAL at specific times during the course of the infection. For example, cultures of BAL fluids were more sensitive than blood cultures or the galactomannan assay in both BAL fluids and serum samples during the initial stages of infection (up to day 3 post intratracheal inoculation). In contrast, at a later stage of infection (at day 5 or 7 post intratracheal inoculation), the galactomannan assay in BAL and serum was more sensitive than cultures (BAL fluids or blood). The results suggest that performance of the galactomannan assay in BAL fluids may be a good indicator of IPA during later stages of infection.

A study by Francesconi et al. (2006), in NZW rabbits showed that antifungal treatment reduced sensitivity of the galactomannan assay in BAL fluids from 100% to 92% in rabbits treated with triazoles (ravuconazole) and polyenes (amphotericin B) compared to untreated rabbits (sensitivity 100%), while specificity remained at 100%. The results suggest that treatment with antifungal agents such as triazoles and polyenes lower the residual fungal load in lung tissue and also diminish the sensitivity of the galactomannan assay in BAL fluids with no overall effect on the specificity.

Three of the animal model studies of invasive aspergillosis also assessed the optimal cut­ off index of the galactomannan assay in BAL. Based on receiver operator characteristic (ROC) curves, the study by Francesconi et al. (2006) in rabbits showed that the optimal cut-off index value in BAL fluids was ≥ 0.75. Studies in mice (Ahmad et al., 2007) and rats (Khan et al., 2008) were based on two cut-off indices and showed that increasing the cut-off value from ≥ 0.5 to ≥ 1.5 decreased the sensitivity between 26% to 52% while retaining the specificity at100%. Overall, the studies in animal models of invasive aspergillosis suggest that a cut-off between 0.5 and 1.0 may be appropriate for testing of BAL fluids.

Clinical Studies A total of twelve clinical studies were reviewed, of which six studies were from patients with hematological malignancies and six studies were from non-hematological populations (Table 1). The EORTC/MSG (2002) criteria were used for a majority of the studies with the exception of two studies [Verweij et al. (1995) and Maertens et al.

(2009)]. Verweij et al. (1995) study was published before the EORTC/MSG criteria were defined, however, the host criteria and radiological criteria, i.e., presence of a pulmonary infiltrate used in Verweij et al., (1995) study were similar to the EORTC/MSG criteria.

Maertens et al. (2009) study defined the proven, probable and possible invasive aspergillosis patients based on the 2008 EORTC/MSG classification scheme. Datasets for Biomarker Qualification Page 5 Galactomannan Detection by Platelia Aspergillus EIA in BAL fluids Mycoses Study Group the study by Husain et al., 2008, which incorporated the results from two solid organ transplant studies (Clancy et al., 2007 and Husain et al., 2007), were available for independent analysis.

In the twelve studies under review, patients with hematologic malignancies had a higher prevalence of the IA compared to the non-hematological populations in BAL fluids (Tables 1A and 1B). The overall sensitivity (range 61 % to 100%) of the galactomannan assay in BAL fluids yielded variable results in different patient populations across the different clinical studies (Tables 1A and 1B). Becker et al. (2003) and Penack et al.

(2008) studies in patients with hematological malignancies showed the highest sensitivity (92% - 100%) of the galactomannan assay. The low sensitivity reported among the hematological patients in one study (Musher et al., 2004) was possibly due to the fact that 75% of patients received systemic antifungal therapy. Similar results were reported in the non-hematological patient population (Meersseman et al., 2008). Thus, it is recommended that a BAL fluid sample be collected, if possible, before anti-fungal treatment is administered.

The sensitivity of the galactomannan assay was higher when a bronchoscopy was performed following positive CT findings resulting in a better prediction for early diagnosis of IPA in untreated patients. Though the sensitivity of the galactomannan assay in BAL was higher than in serum, the correlation of the galactomannan assay results between BAL and serum samples has been discordant. However, none of the studies reported positive results in serum with negative results in BAL. The sensitivity of culture of respiratory specimens for Aspergillus species was approximately 30% in patients with hematological malignancies and hematopoietic stem cell transplants. Detection of galactomannan in BAL fluid was more sensitive than culture and results of the galactomannan assay in BAL fluids were available faster (72 hours) than culture.

Musher et al. (2004) reported that for case patients who were culture-positive, using the galactomannan assay in real time would have yielded an earlier diagnosis in 24 patients, thus indicating the usefulness of galactomannan testing for an earlier diagnosis of IPA.

The available data support the use of a positive galactomannan result in BAL fluid as an indicator for the diagnosis of “probable” invasive aspergillosis.

The specificity of galactomannan assay in BAL fluids varied (range, 79% - 100%) across the studies at a cut-off ≥1.0, which may reflect the heterogeneity of the source population. Increasing the cut-off index values from ≥0.5 to ≥1.0 had minimal effect on sensitivity, however, the specificity of the galactomannan assay improved by 4% in one study (Tables 1A and 1B). The negative predictive value was consistent across studies (96% -100%), suggesting that a negative result correlated with absence of disease. The positive predictive value of the galactomannan assay in BAL fluids ranged from 54% to 100% among the patients with hematological malignancies. However, as shown in the prospective and retrospective cohort studies by Becker et al. (2003), the galactomannan assay in BAL was a better predictor of IPA when used in conjunction with other diagnostic criteria based on the patient’s underlying disease (host factors), clinical and Biomarker Qualification Page 6 Galactomannan Detection by Platelia Aspergillus EIA in BAL fluids Mycoses Study Group radiological diagnostic imaging, and when confirmed by culture or histopathology as described in the EORTC/MSG criteria of 2002.

False positive results should be considered in patients treated with antibiotics produced by Penicillium sp. (ampicillin, amoxicillin, and piperacillin-tazobactam) or electrolyte solutions such as Plasmalyte® used in bronchoscopy. In addition, clinical specimens from non-hematologic patients colonized with Aspergillus species or infected with Histoplasma capsulatum, or other rare invasive fungal infections such as those caused by Penicillium species or Paeliocymyces species have been reported to cross-react with the galactomannan assay. Although cases of Penicillium sp. and Paeliocymyces sp. have not been reported in the studies in patients with hematologic malignancies, it is not clear whether attempts were made to systematically detect fungal species other than Aspergillus for patients enrolled in the study.

Overall, the results from the eleven studies suggest that galactomannan assay in BAL fluid is a useful diagnostic tool provided that the study population is well defined using the EORTC/MSG criteria to identify the population at risk for developing IPA. There was a higher prevalence of IPA in patients with hematological malignancies and HSCT than in patients without hematological malignancies. The studies suggests that the galactomannan assay in BAL would have greater applicability in patient populations at greater risk for IPA infection, i.e. the hematological malignancies population, especially in identifying “probable” invasive aspergillosis patients based on EORTC/MSG criteria.

In addition, the specificity and positive predictive value of the galactomannan assay was higher in neutropenic patients with hematological malignancies and HSCT when compared to non-hematologic patients, for example, solid organ transplant patients.

Based on the clinical and animal model studies of invasive aspergillosis, a cut-off index ≥



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